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Symposium Reports |
1 Molecular and Vascular Medicine Unit; Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Abstract
Plasmalemmal Cl––HCO3– exchangers regulate intracellular pH and [Cl–] and cell volume. In polarized epithelial cells, they contribute also to transepithelial secretion and reabsorption of acid–base equivalents and of Cl–. Members of both the SLC4 and SLC26 mammalian gene families encode Na+-independent Cl––HCO3– exchangers. Human SLC4A1/AE1 mutations cause either the erythroid disorders spherocytic haemolytic anaemia or ovalocytosis, or distal renal tubular acidosis. SLC4A2/AE2 knockout mice die at weaning. Human SLC4A3/AE3 polymorphisms have been associated with seizure disorder. Although mammalian SLC4/AE polypeptides mediate only electroneutral Cl––anion exchange, trout erythroid AE1 also promotes osmolyte transport and increased anion conductance. Mouse AE1 is required for DIDS-sensitive erythroid Cl– conductance, but definitive evidence for mediation of Cl– conductance is lacking. However, a single missense mutation allows AE1 to mediate both electrogenic SO42––Cl– exchange or electroneutral, H+-independent SO42––SO42– exchange. In the Xenopus oocyte, the AE1 C-terminal cytoplasmic tail residues reported to bind carbonic anhydrase II are dispensable for Cl––Cl– exchange, but required for Cl––HCO3– exchange. AE2 is acutely and independently inhibited by intracellular and extracellular H+, and this regulation requires integrity of the most highly conserved sequence of the AE2 N-terminal cytoplasmic domain. Individual missense mutations within this and adjacent regions identify additional residues which acid-shift pHo sensitivity. These regions together are modelled to form contiguous surface patches on the AE2 cytoplasmic domain. In contrast, the N-terminal variant AE2c polypeptide exhibits an alkaline-shifted pHo sensitivity, as do certain transmembrane domain His mutants. AE2-mediated anion exchange is also stimulated by ammonium and by hypertonicity by a mechanism sensitive to inhibition by chelation of intracellular Ca2+ and by calmidazolium. This growing body of structure–function data, together with increased structural information, will advance mechanistic understanding of SLC4 anion exchangers.
(Received 5 October 2005;
accepted after revision 13 October 2005; first published online 20 October 2005)
Corresponding author S. L. Alper: Molecular and Vascular Medicine Unit, E/RW-763 Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. Email: salper{at}bidmc.harvard.edu
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